B08 IDECABTAGENE VICLEUCEL VERSUS STANDARD REGIMENS IN PATIENTS WITH TRIPLE-CLASS–EXPOSED RELAPSED AND REFRACTORY MULTIPLE MYELOMA: KARMMA-3 A PHASE 3 RANDOMIZED CONTROLLED TRIAL
Authors: P. Rodríguez-Otero, S. Ailawadhi, B. Arnulf, K. Patel, M. Cavo, A.K. Nooka, S. Manier, N. Callander, L.J. Costa, R. Vij, N.J. Bahlis, P. Moreau, S.R. Solomon, M. Delforge, J. Berdeja, A. Truppel-Hartmann, Z. Yang, L. Favre-Kontula, F. Wu, J. Piasecki, M. Cook, S. Giralt
Journal: HemaSphere (2023)

Background: Survival outcomes are poor in patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class–exposed (TCE) to immunomodulatory (IMiD®) agents, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies. As patients become TCE in earlier lines of therapy, treatment options are limited. Idecabtagene vicleucel (ide-cel) demonstrated deep durable responses in heavily pretreated TCE RRMM. Methods: KarMMa-3 (NCT03651128), an international, open-label, randomized controlled trial, enrolled patients with RRMM who received 2–4 prior regimens, including an IMiD agent, PI, and daratumumab, and refractory to the last regimen. Patients were randomized 2:1 to ide-cel or a standard regimen (investigator choice of daratumumab + pomalidomide + dexamethasone, daratumumab + bortezomib + dexamethasone, ixazomib + lenalidomide + dexamethasone, carfilzomib + dexamethasone, or elotuzumab + pomalidomide + dexamethasone based on prior regimen). Ide-cel was infused at a target dose of 150–450×106 chimeric antigen receptor-positive (CAR+) T cells (≤540×106 cells allowed). Primary endpoint: progression-free survival (PFS) assessed by Independent Response Committee (IRC). Key secondary endpoints: IRC-assessed overall response rate (ORR) and overall survival. Other secondary endpoints: duration of response (DOR), health-related quality of life (QoL), pharmacokinetics, and safety. Efficacy assessed per ITT. Results: Of 386 patients (ide-cel n=254, standard regimens n=132), 225 received ide-cel (median dose 445×106 CAR+ T cells [range 175–529×106]) and 126 received standard regimens. Baseline characteristics, including median age (63 years), median time since diagnosis (4.1 years), median prior therapies (n=3), triple-class (66%) and daratumumab (95%) refractoriness, and high-risk cytogenetics (44%), were generally balanced. Median follow-up from randomization to data cutoff was 18.6 months. Ide-cel significantly improved PFS versus standard regimens (median 13.3 vs 4.4 months, HR 0.49, P<0.0001). Ide-cel significantly improved ORR versus standard regimens (71% vs 42%, P<0.0001), with deeper (complete response 39% vs 5%), more durable responses (median DOR 14.8 vs 9.7 months). PFS and ORR benefit of ide-cel was consistent across multiple patient subgroups. Post–ide-cel infusion, CAR+ T cells underwent rapid multi-log expansion (median 11 days to maximum expansion). In the treated population, grade 3/4 adverse events (AEs) occurred in 93% and 75% of patients in the ide-cel and standard regimen arms, respectively, and grade 5 AEs in 14% and 6%; grade 5 treatment-related AEs in 3% and 1%. In ide-cel-treated patients any grade cytokine release syndrome occurred in 88%; grade 3/4 in 4%. Any grade investigator-identified neurotoxicity occurred in 15% of patients; grade 3/4 in 3%. Ide-cel demonstrated clinically meaningful improvements on patient-reported outcomes, including symptoms, functioning, and QoL versus standard regimens (Figure). Conclusions: Ide-cel treatment resulted in a significant improvement in PFS and ORR, with deeper and more durable responses versus standard regimens. Ide-cel benefit was consistent across difficult-to-treat subgroups. The toxicity profile of ide-cel was consistent with prior studies. These results support the use of ide-cel in patients with early relapse TCE RRMM, a population with poor survival outcomes. This abstract is an encore previously submitted at ASTCT 2023.